Inefficient targeting of therapeutics is associated with side-effects from off-target activity, and/or poor if any therapeutic efficacy. One area in which targeting is particularly important is immunotherapy, which holds promise as a treatment modality for cancer and infectious disease, among others. Conventional immunotherapy generally involves activating or augmenting a subject's immune system to recognize or more effectively respond to a disease agent. Current approaches include the isolation, activation, expansion, and reintroduction of a subject's T-cells. However, this entire process is both laborious and time-consuming. Cell-expansion processes are limited by the number of cells in a starting sample that recognize a target of interest, if T-cells can even be made to recognize the target in the first place. Expansion to a therapeutically relevant population of target-specific T-cells from a single clone may take months. Moreover, the need for relatively short-lived accessory cells in this process imposes the further need for a replenishing source of such cells, and is accompanied by an increased risk of contamination, such as in the case when the accessory cells carry a virus. Limitations such as these reduce the potential of immunotherapy to treat various conditions, such as cancer.
There are about 200 different types of cancer. Cancers can start in any type of body tissue and can metastasize from one body tissue to another. There are many different causes of cancer and these include; carcinogens, age, genetic mutations, immune system problems, diet, weight, lifestyle, environmental factors such as pollutants, some viruses for example the human papilloma virus (HPV) is implicated in cervical cancer and some bacterial infections are also known to cause cancers. There are many different treatment options for cancer and the treatment sought is often determined by the type and stage of the cancer. Treatment options include; chemotherapeutic drug treatment, hormonal drug treatment, radiotherapy, surgery, complementary therapies and combinations thereof. However, some cancers still have poor prognosis and treatment options.
Acute myeloid leukemia (AML), for example, is the most common type of leukemia in adults, with more than 12,000 new AML cases being reported each year and 9,000 associated deaths occurring annually in the United States. Surgery and radiation therapy have very limited roles in the treatment of this type of cancer because the leukemia cells spread widely throughout the bone marrow and to many other organs. With appropriate induction and consolidation therapy, 60%-70% of adults with AML can be expected to achieve a complete remission. However, the remission tends to be shorter in older patients and relapse is common. Patients with relapsed leukemia have an especially poor prognosis, with a long term disease-free survival rate of only 5-10% without hematopoietic stem cell transplantation. There is currently no standard treatment for patients with relapsed AML, but for a time the most promising drug was a monoclonal antibody drug conjugate, Gemtuzumab. This drug was approved by FDA in 2000 as a single agent for AML patients over 60 years of age who were experiencing their first relapse, or those who were not considered candidates for standard chemotherapy. Unfortunately, Gemtuzumab failed to show evidence of efficacy in the post-approval trial, and was associated with significant hepatotoxicity. It was later withdrawn from the market in 2010. This currently limits the treatment options for relapsed AML patients to hematopoietic stem cell transplants (if one has not already been performed), arsenic trioxide (for the acute promyelocytic leukemia subtype only), participation in clinical trials, or palliative care.
Typical cell-based immunotherapy alternative approaches involve generating immune cells (activated T cells or natural killer cells) that can circulate long enough in patients to engage and destroy cancer cells through their natural cytotoxicity pathways. Some of these approaches involve cancer vaccines, and others involve the genetic engineering of the immune cells to recognize leukemia biomarkers and the use of bispecific antibody T cell conjugates. However, these approaches also have significant limitations, such as substantial production costs and limited number of bispecific antibodies on the surface of cells.